Family planning options, including hormonal contraceptives, are essential for improving reproductive health among HIV-infected women. For these individuals, prevention of unintended pregnancy decreases maternal and child mortality, as well as reduces the risk of mother-to-child HIV transmission. Similarly, antiretroviral therapy (ART) is essential for reducing morbidity and mortality among HIV-infected individuals, in addition to preventing HIV transmission. Thus, it is of critical public health importance to safely combine hormone contraceptives and ART. Millions of HIV-infected women on ART currently use subdermal progestin-releasing implants as a preferred method of long-acting, reversible contraception despite the lack of critically needed pharmacokinetic (PK) drug-interaction data to inform their safe and effective concomitant use. Highlighting this concern, our research team recently demonstrated that combined use of efavirenz (EFV)-based ART, the only preferred first-line ART regimen in low- and middle-income countries, with a levonorgestrel (LNG)-releasing implant for one year reduced LNG plasma concentrations by approximately 50% compared to women not on ART. Importantly, we also observed three unintended pregnancies (15%) in our study group of women on EFV-based ART plus the LNG implant, in contrast to the <1% expected failure rate of the implant for women without drug interactions. Still, subdermal implants remain an essential family planning option and are routinely co-prescribed with ART. Therefore, the overall goal of this proposed study is to build upon and extend our prior work in order to provide comprehensive, evidence-based guidance on the use of LNG implants with ART in HIV-infected women. Overall, we hypothesize that detrimental drug-drug interactions between the LNG implant and EFV-based ART can be overcome by using an increased dose of the LNG implant and/or alternative ART combinations. We will accomplish this through the following three specific aims: Aim 1) determine if increasing the dose of the LNG-releasing subdermal implant effectively overcomes the known PK interaction with EFV- based ART; Aim 2) predict optimal strategies to comprehensively combine LNG implants with ART options using physiologically-based PK (PBPK) modeling; and Aim 3) determine the in vivo PK of LNG released from a subdermal implant over one year in combination with emerging ART strategies. Collectively, these aims significantly extend our preliminary findings to identify a strategy to overcome the drug-drug interaction between LNG and EFV-based ART, advance contraceptive therapeutic options for HIV-infected women, and advance the science of the drug-drug interaction field. Overall, our proposed study will provide an evidence- based approach to safely combine LNG implants with ART regimens spanning the continuum of HIV care. In turn, this collaborative study is strongly expected to improve the management of reproductive health in millions of HIV-infected women worldwide.